Thursday, September 22, 2005


Nature Reviews Neuroscience - Reviews: "Discoveries concerning the molecular mechanisms of cell differentiation and development have dictated the definition of a new sub-discipline of genetics known as epigenetics. Epigenetics refers to a set of self-perpetuating, post-translational modifications of DNA and nuclear proteins that produce lasting alterations in chromatin structure as a direct consequence, and lasting alterations in patterns of gene expression as an indirect consequence. The area of epigenetics is a burgeoning subfield of genetics in which there is considerable enthusiasm driving new discoveries. Neurobiologists have only recently begun to investigate the possible roles of epigenetic mechanisms in behaviour, physiology and neuropathology. Strikingly, the relevant data from the few extant neurobiology-related studies have already indicated a theme -- epigenetic mechanisms probably have an important role in synaptic plasticity and memory formation.

Recently, cellular, molecular and behavioural approaches have led to several exciting developments in the area of epigenetics that specifically concern neurobiological systems. In this review, the topic of epigenetics is introduced. The idea that the conservation of epigenetic mechanisms for information storage represents a unifying model in biology is then discussed, with epigenetic mechanisms being used for cellular memory at different levels that range from cellular differentiation to development to behavioural memory.
Epigenetics is defined as a mechanism for the stable maintenance of gene expression that involves physically 'marking' DNA or its associated proteins, which allows genotypically identical cells to be phenotypically distinct. Epigenetic marking of the genome can take several forms. Methylation of DNA and acetylation, phosphorylation, ubiquitylation and methylation of histones are discussed as potential mechanisms for the epigenetic tagging of the genome.
Neural development and differentiation involve the actions of the RE1-silencing transcription factor (REST), which recruits transcriptional co-factors and ultimately modulates the acetylation of histones.
The master circadian oscillator in the suprachiasmatic nucleus uses epigenetic mechanisms, including histone acetylation and phosphorylation, to generate circadian patterns of gene expression and to modulate gene expression in response to phase-resetting stimuli.
Seizures are known to lead to several lasting changes in gene expression. These changes seem to be due, at least in part, to changes in histone acetylation.
The formation of long-term memories requires a highly coordinated pattern of gene expression. Several recent studies indicate that epigenetic mechanisms are involved in long-term memory formation. Exposure to learning paradigms that result in the formation of long-term memories lead to changes in histone acetylation. Interference with the function of the CREB-binding protein (CBP), which is a histone acetyltransferase, impairs long-term memory formation. Treatment of animals with histone deacetylase inhibitors, which increase levels of histone acetylation, enhances the formation of long-term memories.
Synaptic plasticity is a candidate cellular mechanism that is implicated in long-term memory formation. Induction of synaptic plasticity leads to changes in histone acetylation that are similar to those seen in long-term memory formation. Disruption of normal CBP function leads to deficits in long-term potentiation. Moreover, treatment with histone deacetylase inhibitors ameliorates deficits in long-term potentiation that are seen in animal models of CBP dysfunction, and enhances long-term potentiation in normal animals.
Several diseases of human cognition are reviewed, in which one of the candidate molecular mechanisms involves dysfunction in epigenetic tagging of the genome. Diseases highlighted are Rubinstein–Taybi syndrome, Rett syndrome, Fragile X mental retardation, Alzheimer's disease and schizophrenia."

Jonathan M. Levenson & J. David Sweatt
Nature Reviews Neuroscience 6, 108-118 (2005); doi:10.1038/nrn1604
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